New Method May Overcome EGFR Drug Resistance In Lung Cancer

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Posted on Nov 28, 2018, 1 a.m.

Targeting EGFR gene mutations has been effective for treating lung cancer in some patients, drug resistance however still poses challenges, as many patients will relapse after having experienced long term remission, as published in the journal Nature Medicine.

University of California scientists claim to have figured out why lung cancers have become resistant to EGFR targeting therapies which may lead to new combination strategies. EGFR mutations cause the mechanisms which control cell division to become stuck on, causing abnormal cell proliferation and cancer; drugs targeting these mutations inhibit EGFR and control tumor growth. Gradually tumor cells rewire themselves so they can once more continue to grow without presence of mutated proteins caused by faulty genes.

It was discovered that when acquiring resistance to EGFR inhibitors tumor cells activate Aurora kinase A proteins, which shuts down the ability of cells to commit suicide, guaranteeing tumor cells will survive regardless of what EGFR genes are doing.

Combining drugs that target Aurora kinase with EGFR inhibitors was observed to kill cancer cells permanently and cause lung tumors to shrink in mice. This was discovered when treating multiple EGFR mutated cancer cells with either rociletinib(which had previously failed in Clovis Oncology phase 3 testing) or Tagrisso; eventually the cells stopped responding after which 94 different drugs were tested to see if they could reverse resistance. This is when the combination of rociletinib or Tagrisso with drugs targeting Aurora kinase could kill of the tumor cells permanently.

To observe the effects of combo in a living model drug resistant tumors were transplanted into mice. Animals treated with EGFR inhibitors alone experienced tumor growth; those treated with the combination experienced tumor shrinkage. It was observed that Aurora can’t make tumors grown on its own, rather it provides an escape route for cancer cells to avoid death.

In a fundamentally new pathway for resistance to emerge, Aurora kinase has been associated with drug resistance for the first time. The scientists believe this combination approach may play a key role in re-invigorating more studies on Aurora kinase inhibition. The team have also identified a biomarker that could be used to identify patients most likely to respond. Elevated levels of TPX2 proteins were discovered while studying samples from late stage drug resistant lung cancer tumors.

The scientists will continue to work towards gaining approval to test TPX2 diagnostics along with the drug combination in clinical trials.